Conditioned Media from Adipose-Tissue-Derived Mesenchymal Stem Cells Downregulate Degradative Mediators Induced by Interleukin-1β in Osteoarthritic Chondrocytes

Osteoarthritis (OA) is the most frequent joint disorder and an important cause of disability. Recent studies have shown the potential of adipose-tissue-derived mesenchymal stem cells (AD-MSC) for cartilage repair. We have investigated whether conditioned medium from AD-MSC (CM) may regulate in OA chondrocytes a number of key mediators involved in cartilage degeneration. CM enhanced type II collagen expression in OA chondrocytes while decreasing matrix metalloproteinase (MMP) activity in cell supernatants as well as the levels of MMP-3 and MMP-13 proteins and mRNA in OA chondrocytes stimulated with interleukin- (IL-) 1β. In addition, CM increased IL-10 levels and counteracted the stimulating effects of IL-1β on the production of tumor necrosis factor-α, IL-6, prostaglandin E2, and NO measured as nitrite and the mRNA expression of these cytokines, CCL-2, CCL-3, CCL-4, CCL-5, CCL-8, CCL-19, CCL-20, CXCL-1, CXCL-2, CXCL-3, CXCL-5, CXCL-8, cyclooxygenase-2, microsomal prostaglandin E synthase-1, and inducible NO synthase. These effects may be dependent on the inhibition of nuclear factor-κB activation by CM. Our data demonstrate the chondroprotective actions of CM and provide support for further studies of this approach in joint disease

Estudio Clínico para comparar la eficacia y tolerabilidad de la utilización de velos electrohilados para el tratamiento de pacientes quemados

Introducción: El gold standard del tratamiento quirúrgico de las quemaduras son los autoinjertos de piel parcial. En estudios preclínicos, el uso de un biovelo de ácido poli(láctico-co-glicólico) (PLGA) electrohilado, colocado entre los autoinjertos y su lecho, ha demostrado su potencial para estimular la regeneración dérmica, aumentando el prendimiento y mejorando la calidad de la cicatriz. Adicionalmente, la estructura tridimensional del biovelo y su biodegradabilidad, le confieren un potencial uso como vía de administración de terapias locales. Estas propiedades no han sido todavía evaluadas en ensayos clínicos en humanos. Objetivo: El objetivo principal de este estudio fue comparar intra-individualmente la efectividad y tolerabilidad del biovelo SKINHEALTEX PLGA utilizado junto con autoinjertos de piel parcial para el tratamiento de quemaduras desbridadas frente a autoinjertos de piel parcial solos. Materiales y métodos: Se realizó un ensayo clínico aleatorizado y controlado a doble ciego incluyendo pacientes adultos con quemaduras que requerían tratamiento quirúrgico, durante 4 años (noviembre de 2018 a septiembre de 2022). Cada paciente actuó como su propio control, realizando un seguimiento durante 12 meses. En la zona control se aplicó el autoinjerto, mientras que en la zona tratamiento se interpuso un biovelo de PLGA bajo el autoinjerto. Se midió el porcentaje de injerto prendido de forma clínica, la calidad de la cicatriz utilizando las escalas de Vancouver y de Evaluación de Cicatrices del Paciente y del Observador, y su elasticidad mediante un instrumento basado en la aplicación de presión negativa. También se midió la evolución analítica de los pacientes preoperatoriamente y al mes de la cirugía. Se recogieron los eventos adversos (ensayo clínico fase I-II, seguridad y efectividad). Resultados: El biovelo fue bien tolerado en los 26 pacientes reclutados, no se observaron eventos adversos relacionados con el mismo, ni alteraciones analíticas sugestivas de efectos sistémicos. No se observaron diferencias estadísticamente significativas en el prendimiento de los autoinjertos de piel parcial. Tampoco en la calidad de las cicatrices posteriores, entre el grupo control (autoinjertos de piel parcial solos) y el grupo con autoinjertos y biovelo SKINHEALTEX PLGA. 3 Conclusión: Este es el primer ensayo clínico en el que se investiga la aplicación de un biomaterial electrohilado en el tratamiento de las quemaduras mediante autoinjertos de piel. SKINHEALTEX PLGA es un producto biocompatible y seguro que puede aplicarse como interfaz entre los autoinjertos y el lecho desbridado de una quemadura, sin disminuir el prendimiento de estos. Los resultados de este estudio sugieren el potencial del biovelo como posible forma de administración de terapias locales, encaminadas a aumentar el prendimiento de los autoinjertos o mejorar la calidad de las cicatrices resultantes en pacientes con quemaduras.Introduction: Split-thickness skin autografts are the gold standard for surgical treatment of burns. In preclinical studies, the use of an electrospun poly(lactic-co-glycolide) acid (PLGA) bioveil, placed between autografts and their bed, has shown potential to stimulate dermal regeneration, increase graft take and improve scar quality. This bioveil also has potential as a drug delivery scaffold due to its three-dimensional structure and biodegradability. These properties have not yet been evaluated in human clinical trials. Objective: The primary goal of this study was to compare intra-individually the effectiveness and tolerability of the SKINHEALTEX PLGA bioveil used in conjunction with partial skin autografts for the treatment of debrided burns, compared to partial skin autografts alone. Materials and methods: A double-blind randomized controlled clinical trial was conducted with adult patients with burns that required surgical treatment, for 4 years (November 2018 to September 2022). Each patient acted as their own control, and they were followed for 12 months. In the control area an autograft was applied, while in the treatment area the PLGA bioveil was interposed between the autograft and the bed. The outcome variables were the percentage of graft take, evaluated clinically, the scar quality measured using the Vancouver Scar Scale and the Patient and Observer Scar Assesment Scale, and scar elasticity using a device based on the deformation after applying negative pressure. Blood test variables preoperatively and one month after surgery were also collected, as well as adverse events (phase I-II clinical trial, safety and effectiveness). Results: The bioveil was well tolerated in the 26 patients that were recruited. No adverse events related to the bioveil or laboratory changes suggestive of systemic effects were observed. No statistically significant differences were observed in partial skin autograft take and subsequent scar quality between the control group (partial skin autografts alone) and the autograft and SKINHEALTEX PLGA bioveil group. Conclusion: This is the first clinical trial investigating the application of an electrospun biomaterial in the treatment of burns using skin autografts. SKINHEALTEX PLGA is a biocompatible and safe product that can be applied as an interface between autografts and the debrided bed of a burn, without reducing graft take. The results of this sstudy suggest 7 potential of the PLGA bioveil as a possible route of administration for local therapies that increase graft take of autografts and/or improve the quality of the resulting scars in burn patients

Extracellular Vesicles from Adipose-Derived Mesenchymal Stem Cells Downregulate Senescence Features in Osteoarthritic Osteoblasts

Osteoarthritis (OA) affects all articular tissues leading to pain and disability. The dysregulation of bone metabolism may contribute to the progression of this condition. Adipose-derived mesenchymal stem cells (ASC) are attractive candidates in the search of novel strategies for OA treatment and exert anti-inflammatory and cytoprotective effects on cartilage. Chronic inflammation in OA is a relevant factor in the development of cellular senescence and joint degradation. In this study, we extend our previous observations of ASC paracrine effects to study the influence of conditioned medium and extracellular vesicles from ASC on senescence induced by inflammatory stress in OA osteoblasts. Our results in cells stimulated with interleukin- (IL-) 1β indicate that conditioned medium, microvesicles, and exosomes from ASC downregulate senescence-associated β-galactosidase activity and the accumulation of γH2AX foci. In addition, they reduced the production of inflammatory mediators, with the highest effect on IL-6 and prostaglandin E2. The control of mitochondrial membrane alterations and oxidative stress may provide a mechanism for the protective effects of ASC in OA osteoblasts. We have also shown that microvesicles and exosomes mediate the paracrine effects of ASC. Our study suggests that correction of abnormal osteoblast metabolism by ASC products may contribute to their protective effects

Guía clínica de consenso en el uso de desbridamiento enzimático en quemaduras con NexoBrid®

Introducción y Objetivo: El desbridamiento precoz es la base del tratamiento de las quemaduras. La retirada de la escara durante las primeras 72 horas es la mejor opción para reducir la estancia hospitalaria y los eventos infecciosos. Sin embargo, en muchas ocasiones se compromete la dermis viable necesaria para obtener los mejores resultados estéticos y funcionales, obligando a injertar el lecho. Hay numerosa evidencia acerca de la reducción de las tasas de injerto, la pérdida hemática y el número de intervenciones cuando se utiliza un desbridante enzimático, NexoBrid®. El objetivo de esta publicación es establecer una guía clínica basada en la opinión de los expertos españoles. Material y Método: Se diseñó un panel de 7 expertos de las principales Unidades de Quemados españolas, con más de 350 pacientes tratados, que discutió las diferentes fases del tratamiento con Nexo-Brid® para obtener una guía clínica de consenso acerca de la indicación, uso y manejo del desbridamiento enzimático. Resultados: Se alcanzó un alto nivel de consenso, con más del 70% de acuerdo en cada una de las fases de tratamiento. Todos los aspectos del tratamiento con NexoBrid® fueron discutidos durante la reunión, así como las indicaciones y limitaciones de su uso, incluyendo todas las nuevas evidencias publicadas hasta el momento. También las diversas opciones utilizadas por los diferentes centros de quemados españoles, alcanzando una recomendación global sobre su uso. Conclusiones: Se redactó un documento como guía clínica preliminar sobre el uso de NexoBrid® hasta que se creen nuevas guías basadas en evidencia. No existe ningún otro consenso similar publicado hasta el momento

Topical Administration of a Marine Oil Rich in Pro-Resolving Lipid Mediators Accelerates Wound Healing in Diabetic db/db Mice through Angiogenesis and Macrophage Polarization

Impaired wound healing in patients with type 2 diabetes (DM2) is characterized by chronic inflammation, which delays wound closure. Specialized pro-resolving lipid mediators (SPMs) are bioactive molecules produced from essential polyunsaturated fatty acids (PUFAs), principally omega-3 docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). SPMs are potent regulators of inflammation and have been used to suppress chronic inflammation in peripheral artery disease, non-alcoholic fatty liver disease, and central nervous system syndromes. LIPINOVA® is a commercially available safe-grade nutritional supplement made from a fractionated marine lipid concentrate derived from anchovy and sardine oil that is rich in SPMs and EPA, as well as DHA precursors. Here, we assessed the effect of LIPINOVA® in wound dressing applications. LIPINOVA® showed biocompatibility with keratinocytes and fibroblasts, reduced the abundance of pro-inflammatory macrophages (Mφ1), and promoted in vitro wound closure. Daily application of the marine oil to open wounds made by punch biopsy in db/db mice promoted wound closure by accelerating the resolution of inflammation, inducing neoangiogenesis and Mφ1/Mφ2 macrophage polarization. In conclusion, LIPINOVA® displays pro-resolutive properties and could be exploited as a therapeutic agent for the treatment of diabetic ulcers

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)